Outcomes of 434 dogs with non‐steroidal anti‐inflammatory drug toxicosis treated with fluid therapy, lipid emulsion, or therapeutic plasma exchange

Abstract Background Traditional management of non‐steroidal anti‐inflammatory drug (NSAID) intoxication includes gastrointestinal decontamination, intravenous administration of fluids (IVF), and gastroprotection. Intravenous administration of lipid emulsion (ILE) and therapeutic plasma exchange (TPE) are popular novel therapeutic strategies. Hypothesis Compare outcomes of dogs treated with IVF, ILE, and TPE for NSAID intoxications and evaluate outcome predictors for drug subgroups. Animals Four hundred thirty‐four dogs with NSAID intoxications (2015‐2020). Methods Multicenter retrospective study of ibuprofen, carprofen, and naproxen intoxication. An ordinal outcome was defined as mild gastrointestinal, moderate kidney, or signs of severe central nervous system disease. Results Signs of neurological disease were overrepresented and acute kidney injury underrepresented in the TPE group among dogs exposed to kidney‐ or CNS‐toxic doses (P = .05), though all TPE dogs with signs of neurological disease had evidence of neurotoxicity at presentation. Dogs treated with IVF had a higher maximal creatinine concentration (median, 1.1 mg/dL; range, 0.4‐8.44 mg/dL) compared with IVF + ILE (median, 0.9 mg/dL; range, 0.4‐6.2 mg/dL; P = .01). Increased maximum time to presentation (P < .001), higher baseline creatinine (P < .001) and PCV (P = .007), and absence of induced emesis (P < .001) were associated with greater clinical severity. Ibuprofen toxicosis was associated with more severe clinical signs compared with carprofen (P = .03). Overall survival rate was 99%. Conclusions and Clinical Importance NSAID toxicosis generally carries an excellent prognosis in dogs. Despite similar outcomes of lower incidence of AKI in the TPE group, and slightly lower maximal creatinine concentration in dogs treated with ILE vs IVF alone, ILE and TPE should be considered in the management of severe NSAID toxicosis.

group, and slightly lower maximal creatinine concentration in dogs treated with ILE vs IVF alone, ILE and TPE should be considered in the management of severe NSAID toxicosis.

K E Y W O R D S
carprofen, ibuprofen, ILE, intoxication, naproxen, NSAID, TPE

| INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered for managing acute and chronic pain conditions in human and veterinary medicine. [1][2][3] Their high global prevalence has resulted in them being one of the most commonly reported poisonings in dogs, 1,[4][5][6][7] with dogs being the most commonly affected domesticated species. 1 According to the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC), ibuprofen is the most frequently reported NSAID exposure in animals, followed by carprofen, aspirin, naproxen, meloxicam, and deracoxib. 1 Clinical signs of acute NSAID intoxication range from mild gastrointestinal (GI) disturbances to severe kidney injury, with severe central nervous system (CNS) disturbances arising at maximal exposed doses. 1,8 Additionally, both dose-dependent and idiosyncratic hepatoxicities occur. 1,8,9 Traditional management of NSAID intoxications involves prompt gastrointestinal decontamination, administration of gastroprotectants, and the intravenous administration of fluids (IVF). 1,8 Over the past 10 years, intravenous administration of lipid emulsion (ILE) has gained popularity as a readily accessible and costeffective management strategy for several lipophilic drug intoxications in animals, including NSAIDs. [10][11][12][13] Therapeutic plasma exchange (TPE) has also become more commonly used in the management of NSAID intoxications in dogs. [14][15][16][17][18][19] This technique involves the separation of the cellular components of blood from plasma by either centrifugal or membrane-based TPE, facilitated by either the rotation of a blood chamber or a nonselective membrane filter, respectively. 20 This technique allows for high amounts of protein-bound toxins to be removed from the circulation and replaced with donor plasma, preventing potentially life-threatening consequences associated with NSAID intoxication. 18,20 To date, there are limited evidence-based recommendations within the veterinary literature to guide clinicians in the management of NSAID intoxications with ILE and TPE.
The primary objective of this study was to compare outcomes of dogs treated with IVF therapy alone, or in combination with ILE, TPE, or ILE and TPE for the treatment of carprofen, ibuprofen, and naproxen intoxications. Secondary objectives were to evaluate predictors of outcome for specific drug subgroups and to investigate the sensitivity and specificity of potential thresholds among these predictors. We hypothesized that TPE would be associated with less severe clinical signs compared with IVF therapy alone, and that ILE would also be associated with positive outcomes, though to a lesser degree compared with TPE. Additionally, we hypothesized that time to presentation, maximal exposure dose, and naproxen ingestion would be associated with the development of more severe clinical signs. June 30, 2020. Dogs of any age were considered for potential inclusion. Dogs that were discharged from the hospital and later readmitted for continued supportive care were excluded from the study for ease of data collection, in addition to dogs that were euthanized without treatment, or where elements of their medical records relevant to the study were incomplete. Dogs treated with other extracorporeal modalities (ie, hemoperfusion and hemodialysis) were excluded. Inclusion criteria were limited to ibuprofen, carprofen, and naproxen based on preliminary data review identifying the majority of NSAID intoxications involving these drugs.

| Medical records review
Data recorded from the medical record included signalment, body weight, NSAID type, maximal NSAID dose, maximal time to presentation, clinical signs at presentation, and the following baseline and discharge clinical pathological variables: creatinine, blood urea nitrogen, phosphorus, sodium, potassium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, PCV, total solids, and urine specific gravity. Maximal NSAID dose was defined as the highest possible exposure dose reported in the history. Discharge clinical pathological data was defined as data last obtained before discharge from the hospital, or before death or humane euthanasia. Time to definitive treatment, induction of and success of emesis, and the following treatments were recorded: activated charcoal, H2-receptor antagonist, proton pump inhibitor, and prostaglandin E1 (PG-E1) analog. Predominant IVF rate, duration of IVF therapy, ILE bolus and CRI dose, if  repeated ILE dosing was used, TPE platform, TPE plasma volumes   exchanged, anticoagulation method, and TPE replacement solutions   were recorded in addition to hospitalization time. Maximal creatinine   concentration was recorded, defined as the highest creatinine concentration recorded by either the referring veterinarian or the referral   hospital at any timepoint throughout hospitalization. To account for   overlap among treatments, classification was adjusted to categorize   dogs among one of four groups: IVF alone; IVF and ILE; IVF and TPE; or IVF, ILE, and TPE.
Acute kidney injury (AKI) was defined as a creatinine >1.6 mg/dL, or a rise in creatinine of ≥0.3 mg/dL during a 48-hour time interval with a consistent history, clinical presentation and laboratory evaluation. 22 Acute kidney injuries were graded according to The International Renal Interest Society AKI grading system for animals. 23 Grade I nonazotemic AKI was defined as creatinine ≤1.6 mg/dL with a rise in creatinine ≥0.3 mg/dL, grade II as creatinine 1.7 to 2.5 mg/dL, grade III as 2.6 to 5.0 mg/dL, grade IV as 5.1 to 10.0 mg/dL, and grade V as Survival to discharge was defined as discharge with no recorded rehospitalization for persistent clinical signs pertaining to the same intoxication event. One-year survival was recorded and defined as cases where confirmatory record of euthanasia, death, or survival was present among the medical record 1-year after the date of discharge.

| Statistical methods
Statistical analyses were conducted using R version 4.0.3 with packages AER, ggplot2, and MASS. The Shapiro-Wilk test was used to assess continuous variables for normality. Descriptive statistics consisted of the median and range for all continuous variables given that the majority of the variables were not normally distributed. The count and percentage (%) were used to report frequency data.
For the purpose of examining associations between severity of signs and recorded variables, a cumulative logistic regression model was fit with no clinical signs as the best, followed by signs of GI disease, AKI, and then signs of neurological disease as the worst. Cumulative logistic regression models are used to predict an ordinal response under the assumption of proportional odds, with parallel slopes across all levels of the response. No adjustment was made for animals with multiple clinical signs, they were judged solely by their worst clinical sign for the purpose of statistical modeling. Multivariate models were constructed with forward selection with an entry criteria of P < .10 in an ANOVA comparing the current model to the model with an additional term. The term with the lowest P-value that was not also related to an existent term was selected while only considering terms that would not reduce the number of complete cases drastically (at least a 30% reduction in cases, a complete case being one which has values for all parameters in the model). The multivariate logistic regression models were formulated using variables that were considered to be potentially significant at the univariate level with a coefficient P-value <0.10 as the criteria (Table S1). Time to presentation, time to treatment, maximal exposure dose, baseline creatinine, maximal creatinine concentration, and baseline BUN were transformed using log 10 . Additional models investigating the association between treatment group and outcome were generated after case stratification by GI, kidney, and CNS maximal exposure toxic doses.

| Fluid therapy and lipid emulsion
The median IVF rate for all dogs was 5 mL/kg/hr (range, 1-10 mL/kg/hr).

| Clinical signs
Data pertaining to GI, kidney, and CNS dysfunction throughout hospitalization for ibuprofen, carprofen, and naproxen toxicosis are summarized in Table 4, and the presence of clinical signs throughout hospitalization for each treatment group are summarized in Table 5.   (5) 5/80 (6) 53/434 (12) Signs of neurological disease

| Univariate analysis: Treatment intervention
A significant association was found between treatment and most extreme clinical signs for all dogs, where more severe clinical signs throughout hospitalization were associated with ILE and TPE provision (P = .03). However, a significant association was also found between treatment group and level of toxic dose (ie, GI vs kidney vs CNS), where a higher exposed dose was associated with an escalation in treatment complexity (P < .001). Dogs treated with IVF alone had a significantly higher maximal creatinine concentration (median, 1.1 mg/dL; range, 0.4-8.44 mg/dL) at any point throughout hospitalization compared with dogs treated with IVF + ILE (median, 0.9 mg/dL; range, 0.4-6.2 mg/dL; P = .01). No significant difference in hospitalization length (P = .06) or survival to discharge (P = .15) was found between individual treatment groups. However, dogs undergoing TPE had significantly longer hospitalization times (median, 54 hours; range, 24-264 hours) compared with dogs that did not undergo TPE (median, 48 hours; range, 0-290 hours; P = .04).

| Univariate exposure dose stratification analysis: treatment intervention
Among dogs that consumed any NSAID at a renal-toxic dose, no significant association between TPE usage and severity of clinical signs was identified (P = .42). Among dogs that consumed any NSAID at a T A B L E 2 Clinicopathological findings at presentation of dogs presented for ibuprofen, carprofen, and naproxen toxicosis  Among dogs that consumed any NSAID at a renal-toxic dose, no significant association between IVF + ILE usage and severity of clinical signs was identified compared with IVF alone (P = .46). For dogs that consumed any NSAID at a CNS-toxic dose, no significant association between IVF + ILE usage and severity of clinical signs was identified compared with IVF alone (P = .84). Among dogs that consumed any NSAID at a renal-or CNS-toxic dose, no significant association between IVF + ILE usage and severity of clinical signs was identified compared with IVF alone (P = .31). Among dogs that consumed a renal-or CNS-toxic dose of any NSAID and underwent TPE, the additional use of ILE was not associated with the severity of clinical signs (P = .84).

| DISCUSSION
The aim of this multicenter retrospective study was to compare the outcome of dogs treated with IVF therapy alone, or in combination with ILE, TPE, or ILE and TPE for the treatment of NSAID intoxications. Dogs exposed to high kidney-or CNS-toxic doses of NSAIDs had a lower incidence of AKI throughout hospitalization when treated with TPE, and the addition of ILE to fluid therapy was associated with a lower maximal creatinine concentration. Though signs of neurological disease were overrepresented among dogs exposed to kidney-or CNS-toxic doses of NSAIDs and treated with TPE, this reflected the degree of toxicosis rather than intervention as all dogs were presented with neurological derangements before therapy. Dogs receiving ILE or TPE had more severe clinical signs throughout hospitalization when maximal exposure dose was not considered.
However, this finding was no longer significant after stratification for exposure dose.
Fifteen percent of dogs treated with IVF + ILE in our study developed kidney injury, while 7% developed signs of neurological disease.
The use of ILE was found to reduce the maximal creatinine concentration in dogs compared with those treated with IVF alone. However, the clinical relevance of this finding is questionable as both medians remained within the normal range for dogs. In vitro lipemia has a negative bias on creatinine measurement in dogs, which might have contributed to this finding. 24,25 However, post-prandial lipemia does not markedly influence serum creatinine concentrations in dogs. 26 Kidney injury was present in 30% of dogs treated with TPE in our study. The incidence of AKI was lower among this cohort if exposed to kidney-or CNS-toxic doses compared with dogs that did not undergo TPE. Signs of neurological disease were present in 5% Increased maximum time to presentation was associated with the development of more severe clinical signs, with a threshold >7.5 hours being a moderate predictor for AKI development. A similar association exists between a longer time from ingestion to intervention with a greater risk of GI ulceration and severe AKI in dogs treated conservatively for ibuprofen toxicosis. 27 While a recent study failed to identify an association between outcome and maximum time to presentation after multivariate analysis, increasing time from ingestion to admission F I G U R E 3 Stacked area chart displaying the effect of baseline packed cell volume (%) on the cumulative probability of developing signs of gastrointestinal, acute kidney injury, and neurological disease in dogs presented for non-steroidal anti-inflammatory toxicosis after cumulative logistic regression modeling. AKI, acute kidney injury; CNS, central nervous system; GI, gastrointestinal F I G U R E 4 Receiver operating characteristic (ROC) curve for maximal time to presentation to predict the development of an acute kidney injury in dogs presented for non-steroidal anti-inflammatory toxicosis. AUC, area under the curve; the identified point represents a maximal time to presentation threshold of 7.5 hours that was found to have a maximized sensitivity and specificity for the prediction of an acute kidney injury or signs of central nervous system disease. Dogs diagnosed with an acute kidney injury at presentation were not excluded from the ROC analysis was associated with the development of both AKI and suspected GI ulceration at the univariate level. 28 Packed cell volume has been associated with the duration of hos- Subsequently, this resulted in artifacts when interpreting the odds of clinical sign development for individual animals. Furthermore, it is also important to recognize the limitations associated with the high number of statistical comparisons performed in this study, despite the application of a Bonferroni correction to pairwise comparisons of treatment groups. As such, the authors caution overinterpretation of this study's significant findings as they might be associated with a type I statistical error. All but one veterinary hospital was equipped to perform TPE. As such, it might not be appropriate to extrapolate findings among this cohort of dogs to all veterinary facilities. Given the cost associated with increasing treatment intervention, an unconscious selection bias might also be present in this cohort of dogs related to owner financial capabilities. Moreover, this selection bias is complicated by the phenomenon of confounding-by-indication, where dogs exposed to higher toxic doses were more likely to be treated with either ILE or TPE, because of a greater clinical concern for morbidity and mortality. 33 As a retrospective study, the data acquired are inherently limited by their availability and accuracy within the medical record. Time to presentation and maximal exposure dose were provided as estimates and were associated with a margin of error.
Comorbidities and a comprehensive list of medications were also not evaluated. Baseline data pertaining to evidence of AKI at presentation was limited by an inability to adequately distinguish pre-renal and renal azotemia in many cases. Furthermore, creatinine and BUN are insensitive markers of kidney function. As such, early kidney injury might not be detected, and improvement or decline in kidney function is hard to assess. The accuracy of clinical pathological data was also limited by the use of multiple analytical devices. Assessment of GI dysfunction was limited to clinical signs in this study and the presence of subclinical GI changes cannot be ruled out. With regards to outcome analysis, the high survival rate of 99% means there was insufficient power to evaluate for associations with death, and lack of true drug exposure might have contributed to this finding. This is similar to the previous reported survival rate of 96% for NSAID overdose in dogs. 28 Non-steroidal anti-inflammatory drug toxicosis generally carries an excellent prognosis in dogs and despite similar overall outcomes, ILE and TPE should be considered in the management of severe NSAID toxicosis.